Stable nimodipine parenteral formulation

Abstract

A nimodipine injection concentrate and diluted formulation comprises nimodipine (base or salt), an effective amount of a hydrophilic surfactant, and a pharmaceutically acceptable carrier for injection which is an aqueous solution, an organic solvent, an oil, or a cyclodextrin, such that the nimodipine is substantially contained in a concentrated injection solution, suspension, emulsion or complex as a micelle or a colloidal particle or an inclusion complex and the formulation is stable and clear. In certain embodiments, the hydrophilic surfactant is polysorbate 80.

The invention claimed is: 
     
       1. A nimodipine injection concentrate formulation consisting of nimodipine base or a pharmaceutically acceptable nimodipine salt in a concentration from about 0.01 to about 5 mg/ml; ethanol; a water for injection; an optional preservative; and an effective amount of a single hydrophilic surfactant which is polysorbate 80 and the polysorbate 80 is from about 6% to about 10% of the injection concentrate formulation, such that nimodipine in the injection concentrate formulation is contained in micelles and the formulation is stable and clear and stored in a container wherein the dissolved oxygen content is about 2 ppm and the head space oxygen content is less than 5%. 
     
     
       2. The nimodipine injection concentration formulation of  claim 1 , wherein the total volume of the concentrate formulation is from about 1 ml to about 10 ml. 
     
     
       3. The nimodipine injection concentrate formulation of  claim 1 , wherein the nimodipine injection concentrate when diluted with a pharmaceutically acceptable aqueous injection medium allows for administration of a single 250 ml infusion bag or bottle that contains less than 2% w/v ethanol, the diluted injection medium remaining a dear micellar solution that displays no precipitation of nimodipine. 
     
     
       4. The nimodipine injection concentrate formulation of  claim 1 , further comprising an effective amount of a preservative selected from the group consisting of cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, benzethonium chloride, boric acid, p-hydroxybenzoates, phenols, chlorinated phenolic compounds, alcohols, quarternary compounds, mercurials, and mixtures of any of the foregoing. 
     
     
       5. The nimodipine injection concentrate formulation of  claim 1 , which is diluted to a volume from about 50 ml to about 1000 ml with a pharmaceutical acceptable carrier for injection such that the nimodipine is present in a concentration from about 0.01 mg/ml to about 1.0 mg/ml, and the ethanol is less than 2% w/v of the formulation, the nimodipine being substantially present in the form of micelles, the diluted formulation remaining clear micellar solution and displaying no crystal precipitation of nimodipine. 
     
     
       6. The nimodipine injection concentrate formulation of  claim 1 , wherein the median particle size of micelles containing nimodipine ranges from about 0.5 nanometer to about 350 nanometers. 
     
     
       7. The nimodipine injection concentrate formulation of  claim 5 , wherein the median particle size of micelles containing nimodipine ranges from about 0.5 nanometer to about 350 nanometers. 
     
     
       8. The nimodipine injection concentrate formulation of  claim 1 , which is prepared by mixing the nimodipine base or a pharmaceutically acceptable nimodipine salt with the ethanol; adding the hydrophilic surfactant to the mixture of nimodipine and ethanol; and thereafter adding from about 0.5 ml to about 4 ml of water for injection to prepare a nimodipine concentrate formulation wherein nimodipine is contained in micelles; and storing the formulation with degassing to provide an dissolved oxygen content of about 2.0 ppm and headspace replacement with an inert gas. 
     
     
       9. The nimodipine formulation of  claim 5 , wherein the ethanol is less than 1% w/v of the formulation. 
     
     
       10. The nimodipine formulation of  claim 5 , which has a pH from about 4.5 to about 8. 
     
     
       11. The nimodipine injection concentrate formulation of  claim 1 , which is stable when exposed to conditions of 40° C.±2° C./75% RH±5% RH for at least 3 months; or which is stable when exposed to conditions of 25° C.±2° C./60% RH±5% RH for at least 12 months. 
     
     
       12. The nimodipine formulation of  claim 5 , which is chemically stable for at least 48 hours for continuous infusion. 
     
     
       13. A nimodipine injection formulation consisting of nimodipine base or a pharmaceutically acceptable nimodipine salt; ethanol; a pharmaceutically acceptable aqueous carrier selected from the group consisting of sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water for injection, dextrose, Lactated Ringers injection, and total parenteral nutrition (TPN); and an effective amount of a single hydrophilic surfactant which is polysorbate 80 and the polysorbate 80 is from 0.01% to about 2.5% w/v of the formulation, such that nimodipine in the injection formulation is contained in micelles and the formulation is stable and clear and stored in a container wherein the dissolved oxygen content is about 2 ppm and the head space oxygen content is less than 5%. 
     
     
       14. The nimodipine injection formulation of  claim 13 , which is diluted to a volume from about 50 ml to about 1000 ml with the pharmaceutical acceptable carrier such that the nimodipine is present in a concentration from about 0.01 mg/ml to about 1.0 mg/ml and the ethanol is less than 2% w/v of the formulation, the nimodipine being substantially present in the form of micelles, the diluted formulation remaining clear micellar solution and displaying no crystal precipitation of nimodipine.